Our Research Portfolio

The Alzheimer's Drug Discovery Foundation (ADDF) publishes all programs that we fund in our research portfolio. Funded research projects can be viewed by the year of funding or by program area, and can also be found by searching for an investigator or certain keywords. Please note that your search term(s) must contain at least four characters.

Additionally, please note that grant funding priorities at the ADDF change over time. The ADDF maintains strict confidentiality with all of our funded projects and cannot share additional information on projects without permission from the investigator(s).

The ADDF does not recommend one particular clinical trial or research program over another. The ADDF is not responsible for the accuracy of the information provided, the selection of research subjects (patients) or the conduct of the clinical trial, treatment IND/expanded access program or other research program.

Improvement of a Novel Abeta-Fibrinogen Interaction Inhibitor to Treat Vascular and Cognitive Defici

Drug Discovery, Vascular and Cholesterol

$150,000

Duration: 7/8/2015-7/8/2016

Abstract:

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to profound cognitive decline. The incidence of the disease is increasing and there are no effective treatments available, so new insights and therapies are sorely needed. Many AD patients suffer from altered cerebral blood flow, damaged cerebral vasculature, and abnormal hemostasis. Circulatory deficiencies could therefore play an important role in this disease. Recently, fibrinogen, the primary protein component of blood clots, has been identified as a strong cerebrovascular risk factor in AD. Fibrinogen specifically binds to the amyloid-beta (Abeta) peptide, altering fibrin clot structure and delaying clot degradation. We identified a novel inhibitor of this interaction using high throughput screening. Long-term treatment with this molecule significantly reduced AD pathology and improved cognition in mouse models of AD. These results suggest that inhibitors targeting the Abeta-fibrinogen interaction show promise as a therapy for AD. We are in the process of improving upon this molecule so that it is more potent and less toxic, strengthening the likelihood that it can be used in humans for AD treatment.

New Inhibitors of kynurenine-3-monooxygenase for Alzheimer's disease therapy

Drug Discovery, Neuroprotection, Inflammation

$145,157

Duration: 6/15/2015-6/15/2016

Abstract:

Alzheimer's disease (AD) is a debilitating neurodegenerative condition that dramatically reduces the ability of those with the disease to function independently with latter-stage disease characterized by severe memory loss, personality disintegration, hostility, anxiety and depression.

Although several drug therapies are currently available, none are particularly effective and offer patients only modest or short-term improvements in symptoms. Hence, there is a significant need for new and improved drug therapies.

We have identified a key metabolic pathway that is implicated in brain injury in AD and other neurodegenerative conditions. This metabolic pathway is known as the kynurenine pathway of tryptophan metabolism. Under normal conditions this pathway produces metabolites that help the brain use energy and mop-up harmful free radicals that can cause cellular damage. However, in disease states such as AD the kynurenine pathway is disturbed and produces a metabolite that damages key components of the central nervous system.

Over many years of research, it has been shown that this key neurotoxic metabolite is quinolinic acid (QUIN). Our team was among the first to show that excessive levels of QUIN kills neurons and other 'helper' cells in the brain and we have extensively investigated the mechanism/s by which QUIN is toxic. Importantly, we have identified a key step in the kynurenine pathway before QUIN is produced that uses the enzymatic catalyst kynurenine 3-monooxygenase (KMO). Without KMO working properly, neurotoxic QUIN cannot be produced. Hence, our work aims to find new drug inhibitors of KMO thereby preventing QUIN neurotoxicity.

To achieve this, we will initiate a drug discovery project that will make use of the latest state-of-the-art drug discovery technology known as 'high-throughput screening'. This technique will identify, from thousands of drug candidates, the most potent drug inhibitors of this key enzyme. This could potentially lead to new drug therapies for AD.

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2015

Tamara Maes, PhD

Oryzon Genomics S.A.

Preclinical development of ORY-2001, a dual LSD1/MAOB inhibitor for the treatment of Alzheimer disea

Clinical Research, Cognitive Enhancers

$270,000

Duration: 5/15/2015-5/15/2016

Abstract:

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Epigenetic modifications may play a role in the onset and progression of these diseases. REST is a key transcription factor that modulates the expression of key neuronal genes.. It binds to its DNA targets and assembles a transcriptional repressor complex containing HDAC1/2, CoREST and LSD1 among others. Inappropriate REST activity in neuronal cells is expected to repress the expression of key neuronal genes like BDNF. Rest mRNA expression is up-regulated in AD and inversely correlated with Uchl1 expression a proteasome biomarker related with neurodegenerative diseases ad AD, PD, FTD and others. Our strategy is to redress transcriptional changes or imbalances in AD by inhibition of components of the REST repressor complex. We chose LSD1. We have developed ORY-2001, a dual LSD1/MAO-B inhibitor, with excellent pharmacological and ADME-PK properties. We have shown that 2 - 4 months of oral treatment with ORY-2001 stops the cognitive impairment and restores the memory deficit of SAMP-8 AD model mice. In the current project, we propose to develop an adequate human formulation for oral once-daily administration, to perform the regulatory toxicology IND-enabling studies and to prepare the whole regulatory package to obtain the IND/CTA permissions to start a Phase I clinical trial in humans and to to develop the clinical plan for ORY-2001.

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2015

Carmela Abraham, PhD

Boston University School of Medicine

Development of Klotho Enhancers as Novel Therapeutics for AD (Follow-On Funding)

Drug Discovery

$236,516

Duration: 5/15/2015-5/15/2016

Abstract:

The anti-aging gene Klotho was named after the Greek Goddess who spins the thread of life. Klotho was discovered in a mouse that showed many manifestations of human aging, including cognitive decline. In contrast, mice that are genetically engineered to express high levels of Klotho live 30% longer. In the brain Klotho's role is entirely unknown. We found that the Klotho protein is significantly reduced in the brain white matter of aged mammals. The long-term project was to identify what causes cognitive decline in 50% of, otherwise healthy, individuals as they age.

Our findings indicate that the Klotho protein induces the maturation of brain cells responsible for the production and maintenance of myelin. Myelin, the fatty layer that insulates nerve extensions allowing nerve cells to communicate with each other efficiently, is produced in the brain only by specialized cells called oligodendrocytes, and only by mature oligodendrocytes. The mature cells are derived from oligodendrocyte precursor cells in the presence of specific growth factors. We hypothesized that the precursor cells need Klotho as a growth factor to become mature, myelin-producing oligodendrocytes. This discovery is of particular relevance to understanding what causes white matter abnormalities in Alzheimer's disease and failed repair of myelin in multiple sclerosis.

We then screened 150,000 small compounds and identified a number of lead compounds able to elevate Klotho protein expression.

Next step is to test whether optimized Klotho-enhancing compounds have the potential to induce the maturation of oligodendrocyte precursor cells, first in the petri dish. The results will directly lead to in vivo testing of optimized compounds in animal models of Alzheimer's disease and multiple sclerosis. These studies are expected to provide a better understanding of the functions of Klotho in myelin biology, and lead to ways to protect brain myelin against age-dependent and pathological changes.

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2015

Chien-Liang Lin, PhD

Ohio State University

Development of small molecule activators of glutamate transporter EAAT2 translation for AD (Year 2)

Drug Discovery

$244,008

Duration: 5/1/2015-5/1/2016

Abstract:

The glial glutamate transporter EAAT2 is responsible for maintaining low extracellular glutamate concentrations and preventing excess glutamate-induced toxicity. Loss of EAAT2 protein and function is commonly found in Alzheimer's disease (AD) patients and is an early event in the disease pathology. Impaired clearance of glutamate in the extra-cellular space raises glutamate levels around synapses of the neurons. Studies indicate that when neurons are activated by high glutamate concentrations for a long period of time they can increase amyloid &#946; production. Our laboratories previously executed high-throughput screening to search for compounds that increase EAAT2 expression via translational activation. This screen and subsequent studies resulted in three lead compound series. We recently evaluated a compound from one of series in APPSw/Ind mice and found that this compound could restore memory and learning, restore synaptic integrity and reduce amyloid plaque after short-term treatment. This compound series warrant further investigation as potential therapeutics for AD. The goals of this study are to further develop this lead series to obtain potential clinical candidates and to understand the underlying mechanisms of compound action.

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2015

Miri Polachek

Israel Brain Tech

BrainTech 2015

Conferences

$2,500

Duration: 3/11/2015-3/12/2015

Abstract:

The conference program aims to address the full life-cycle of braintech innovation - from research to commercialization - and facilitate global collaboration towards solutions that will improve millions of lives.

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2015

Deborah Blacker, MD, ScD

Harvard Medical School

Alzheimer's Disease Modifiable Risk Database

Prevention and Risk Factor Interventions, Nutrition & Diet

$25,000

Duration: 2/1/2015-2/1/2016

Abstract:

This is a proposal to extend the current support on our Alzheimer's Modifiable Disease Risk Database and to add two new entries to the site. The prior support was for entries on the impact on AD risk of statin use (complete, to be posted once a companion manuscript is in press) and blood lipid levels (well underway). The proposed support is for entries on vitamin D intake and on blood pressure control and specific blood pressure medications. This database, known as AlzRisk, is an online compendium of environmental risk factors for Alzheimer's Disease hosted by the Alzheimer Research Forum (www.alzforum.org). It was developed in collaboration with AlzForum web developers, and aims to provide systematic review, cataloguing, and meta-analysis (where feasible) of the impact of these risk factors in the context of a rigorous methodological discussion. It is intended as a resource for the Alzheimer's disease research community, similar to AlzGene, AlzForum's online compendium of Alzheimer's disease genetics findings which served as an early model for the site. AlzRisk offers a compendium of risk factor data on 10 risk factors, with several more in the pipeline. Each entry includes a systematic review of the prospective cohort data in tabular form and a rigorous methodological discussion of the strengths and limitations of the evidence, and a "Current Understanding" text that gives the bottom line for each. Where feasible, we include a meta-analysis of the available data. Such information can be used to plan follow up research and clinical trials, to assess personal risk, to support medical recommendations and public health practice, and to generate a comprehensive risk profile to guide prevention efforts.

This proposal involves the search for compounds for the treatment of Fronto-Temproal Dementia that increase the amount of a key neurpprotective molecule in the brains of FTD patients. Sortilin is involved in the degradation of Progranulin ("PGN"), an anti-inflammatory molecule whose mutation leads to familial FTD. Sortilin decreases extracellular concentrations of PGN, and thus decreases PGN's ability to act as a neuroprotective anti-inflammatory molecule protecting neurons against cell-death. The utility of compounds that selectively prevent the endocytosis and degradation of PGN by Sortilin as possible therapeutics for FTD has previously been proposed. This project proposal involves the development of assays using Sharp Edge Labs' proprietary screening platform to screen for compounds that can selectively inhibit Sortilin-dependent PGN endocytosis, without altering Sortilin's trafficking of other molecules important for neural survival and health (e.g. ApoE).